Members of the epidermal growth factor receptor family (ErbB1/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4) are transmembrane tyrosine kinases that are activated by ligand-induced dimerization. These receptors regulate cell proliferation, differentiation, and migration, and their abnormal activation is associated with a variety of human cancers. Several cancer drugs interact with the ATP-binding site of the EGFR kinase to halt tumor growth and increase apoptosis in cancer cells.
Compounds that directly inhibit the kinase activity of the EGFR, as well as antibodies that reduce EGFR kinase activity by blocking EGFR activation have been used as anti-cancer therapeutics. Such therapeutics are not effective for many EGFR-related illnesses or are not effective against certain patient populations. Additionally, efficacy of anti-EGFR therapeutics is limited by the invariable development of primary or acquired drug resistance.
The present inventors have discovered a new nuclear transcriptional network involving the KLF6 and FOXO1 tumor suppressor genes that regulate response to anti-EGFR-based therapies. The discovery has led to new and improved therapies for treatment of cancer.